JPS5953490A - 7-oxo-4-oxa-diazabicyclo(3,2,0)hept-2-ene derivative - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention provides novel 7-oxo-4-oxa-2,6-diazabicyclo[
3,2,0]]hept-2-ene derivatives and their use as intermediates and in particular for the synthesis of β-lactam antibiotics.

It has already been shown that N-substituted oxazodinoazetidinones are suitable for the stereospecific synthesis of 1-oxazothia-3-cephem-4-carboxylic acids by intramolecular cyclization (T, Aolciet al,
l1eterocycles 15 (1981) 4
09; T, Aoki et al, Tetrah
edron Lett, (197, 9) 4.327
iGerman patent application publication) 1F! No. 2, 806.
No. 457 and No. 2.800.860).

Furthermore, azetidinones in which the nitrogen atom is unsubstituted are known to readily react with fik-type electrophiles [for example, I? , /
J.

Woodward at at, J, Am, Ch.
, em, Soc, 88 (1966) 852: French Patent No. 1.495.047].

From these points of view, oxazolinoazetidinones in which the nitrogen atom is missing represent highly desirable compounds in the production of β-lactam antibiotics.

However, attempts to declare these as i+''!, t+, f have not been successful (7?, J,
5toodlay.

proc, of th, e, 5evttnth W
orkshop Conf.

11oechst, 5chloss Reisens
burg, (1978) 193-203), I?
, J., 5toodley, J.

Elks, I? escent nodvances
in the Chemistry of β
-Lactan1. Antibiotics, Th
e Chemical Society London
(1977), 189].

The present invention is based on the general formula +1+ () where R is hydrogen or optionally substituted alkyl, alkenyl, alkynyl, aralkyl, aryl,
Representing heteroaryl, heteroaralkyl, aryloxyalkyl, heteroaryloxyalkyl, alkoxyalkyl, arylthioalkyl, heteroarylthioalkyl, alkylthioalkyl, alkoxy, aryloxy, alkylthio or arylthio, provide

These new compounds, in which the nitrogen atom is unsubstituted, react with both -functional and difunctional reagents to form β in a more flexible manner than the N-substituted derivatives mentioned above.
- Has the advantage of being able to control lactam antibiotics. This type of synthesis of β-lactam antibiotics is intensive and therefore effective.

Due to the initial absence of the N-substituent, the spectrum of the target compound of interest is clearly broadened.

Compounds according to the invention 1, (a) general formula (2) in which R has the meaning given above and Co, E represent an acid function Co, II or any desired ester group; , where Ef represents an acid protecting group commonly used in β-lactam chemistry, preferably an 01-C4-alkyl group, in a suitable solvent or solvent mixture. Then, in the presence of an acid binder, solvo-lytic decomposition (5olvo-lytic)
or (b) general 〒v; +3+ where R and CO! E has the meaning -1-, which can be obtained by the process of converting the oxyamide of in a suitable solvent or solvent mixture, if appropriate in the presence of an acid or a base, under solvation conditions. can.

The compound of general formula (2) in which R, Co, and E have the above-mentioned meanings can be prepared, for example, by Y in the same manner as in known methods.

Maki et al., J.C.S., perkin.
+ (1981) 2, 087, Y, JIamashi
tna et a, 1. , Tetrahe-dro?
1. Lett, (1979) is 9 s, 5.1
lyeo etat,, J, Am, Chem, Soc
, 101, 4,403 (1979) and Belgian Patent Office No. 862.793. It can be obtained by subjecting it to isomerization in a suitable solvent and in the presence of a base.

Similarly, the oxacylinooxyamide of general formula (3) is prepared using R and CO! The olefinic bond of the azetidinone of the general formula (2) in which E has the above meaning is defined, for example, in German Patent Application Publication No. 2. l'
t 39.646, European Patent No. 21,676, Peruvian Patent No. 849.118 and S, Ya
tnamoto et al.
las 8°282 (1977) and A1. Nari
Sada et al.

J. Med. Chem. 22.757 (1979)
.

Hgterocyc1g87, Fl 39 (19
77), it can be obtained by subjecting it to oxidative cleavage.

Furthermore, the compound of general formula (2) can be prepared in the same manner as in other known methods according to the literature, for example, in Japanese Patent Publication No. 55-047, 68.
Publication No. 7 or Netherlands/If i4'l No. 7,3
13, No. 896, or Y, l1rrrnashi? I
7a et at,.

Ttrahedron Lett, (1979) 4.
It can be manufactured by the method described in 943.

If appropriate, as possible starting materials for the optically active oxazolinoazetidinones of the general formulas (I S, 5 /? ) (1) and (IR15S ) (1), compounds of the general formula (4 ) is used.

There are two examples in the literature for the synthesis of two enantiomers of a compound of general formula (4) in which R is phenyl: (I S, 5 R) (4): S, Yarn, amo
to at at at.

Tetrnhedron LgH, (1981) 3,
089 (IB, 55) 14): Y, IIarr
tashitna at al.

Tgtrahedron Lett, (1979) 2
, 595 Other compounds (1) can be produced in a similar manner.

For example, methyl 2-[(IS,5R)-3-benzyl-7
-oxo-4-oxa-2,6-diazabicyclo[3,
When using 2,0]]hept-2-en-6yl]-3methylbut-3-enoate (4(Z), the reaction process for producing compound (1) according to the present invention can be expressed by the following reaction formula. Can be: Co2C, 113 ° f = In the compounds of the general formula fil, (2), (3) and (4), optionally substituted alkyl (j preferably having 1 to 7 C atoms) Straight button shape, branched tin shape, i
, (formula ii is a raw hydrocarbon group. Alkyl M tj: J
, % and 1' can also be substituted with a halogen, preferably chlorine, hydroxyl, amine, carboxyl, carbamoyl, or carbamoyl"!, tan (more details below "L may be mono- or di-substituted with optionally substituted aryls and heteroaryls as defined in .In particular methyl, halogenomethyl, tg
Mention may be made of radicals such as rt-aryl, cyclohexyl and cyclohexagenyl.

optionally substituted aryl is phenyl;
The phenyl is preferably methyl, ethyl, aminomethyl, hydroxyl, methoxy, ethoxy, carbamoyloxy, acetoxy, amine, mesylamino, methylamino, aminosulfonylamino, amidino, mesyl, methylsulfinyl, methoxycarbonyl, carbamoyl,
It may be mono↑4-substituted or di-substituted or, if appropriate, di-substituted, with sulfo, methylthio, silyl, silyloxy halogen.

Optionally substituted aralkyl is a combination of the meanings given above for aryl and alkyl. The following may be mentioned in particular: benzyl, p-hydroxybenzyl, p-aminobenzyl, α-aminobenzyl, α,4-diaminobenzyl, α-amino-4-hydroxybenzyl, α-carboxybenzyl, α -carboxy-4-hydroxybenzyl and bis-(trimethyllysilyl)-carboxy-4-hydroxybenzyl.

optionally substituted heteroalkyl 5M;

contains 1 to 4 heteroatoms, i.e., oxygen atoms, hydrogen atoms or sulfur atoms, and is not fp7-substituted, or methyl, ethyl, hydroxyl, oxo, amino, imino, mesyl, mesylamino, silyl, Any unsaturated 5- or 6-membered compound which may be -, di- or tri-substituted with carboxyl, carbamoyl, acetyl or halogen? Represents a ring 14'l structure.

Unsaturated optionally substituted heterocyclic rings are preferably 1-furyl, methylfuryl, thenyl, methylthenyl, 2-aminothiazolyl, thiazolyl, methylinxazolyl, isoxazolyl, pyridyl, 2-aminopyridyl, pyrimidyl, pyrazolyl. , uracil, thiadiazolyl, tetrazolyl or pyranyl group.

Optionally substituted heteroalkyl preferably has a combination of the meanings mentioned for alkyl and heteroaryl. Especially furylmethyl, thenylmethyl, 2-aminothiazolylmethyl, thiazolylmethyl,
Aminopyridylmethyl, 1-amino-1-11-tetrazol-5-yl-thiomethyl, 2-aminothiazolyl-
Mention may be made of methoxyiminomethyl and 1-(2-aminothiazolyl)-prop-1-enyl.

Aryloxyalkyl, heteroaryloxyalkyl and U-alkoxyalkyl, which may be replaced with 11 at any time, are the above-mentioned except that they have an oxygen bridge in the form of an ether function between the alkyl moiety or the alkyl moiety and the aryl or heteroaryl moiety. has the meaning of The following may be mentioned in particular: phenoxymethyl, 4-hydroxyphenoxymethyl, α-aminophenoxymethyl, α-amino-4-hydroxyphenoxymethyl, methoxymethyl, tert-butoxymethyl, thenyloxymethyl, α- Aminothenyloxymethyl, furyloxymethyl and α-aminofuryloxymethyl.

Optionally substituted arylthioalkyl, heteroarylthioalkyl and argylthioalkyl,
A surface bridge in the form of a thioether function between the alkyl moiety or the alkyl moiety and the aryl or heteroaryl moiety (115) has the above meaning. In particular, mention may be made of: Phenylthiomethyl, 4-hydroxyphenylthiomethyl, α-aminophenylthiomethyl, 2-methyl-1-thia-3,4-
Diazol-5-ylthiomethyl, methylthiomethyl and t-butylthiomethyl.

Alkoxy or aryloxy, optionally substituted, represents an alkyl or aryl group as defined above and bonded directly via an oxygen bridge. Mention may be made in particular of dimethoxy, ethoxy, tert-butoxy, phenoxy, benzyloxy, diphenylmethoxy, 4-nitropenzyloxy and 4-methoxybenzyloxy.

Optionally substituted alkylthio or arylthio is as defined above and 4i' represents an alkyl or aryl group bonded directly via a yellow bridge. The following may be mentioned in particular: meglthio, ethylthio, tert-butylthio, phenylthio, benzylthio, diphenylmeglthio and 4-nitrobenzylthio.

Examples of the novel oxazolinoazetidinone of formula (1) according to the present invention include the following compounds.

Suitable reagents in converting compounds of formula (4) to compounds of formula (2) are any of the common organic and inorganic bases.

These preferably include alkali metal hydroxides, alkali metal oxides, arunonorimetal amides, and amines such as potassium hydroxides, triethylamine, triethylamine,
Diisopropylethylamine, pyridine, dimethylaniline, diethylamine and 1,5-diazabicyclo(5
,4,0) undec-5-ene(I)BU), or I
)13N and ammonia are particularly suitable.

Suitable diluents are any inert organic solvents and organic bases and water. These preferably include ethyl acetate,
Includes tetrahydrofuran, dichloromethane, dichloroethane, dichlorobenzene, toluene, ethylamine and dimethylamine. Isomerization is generally -50 to +5
It is carried out at a temperature between 0°C, but preferably between 0°C and room temperature.

In the conversion of compounds of formula (2) to compounds of formula (3), suitable reagents are any common oxidizing agents capable of cleaving olefinic double bonds in the manner described above.

Especially sodium periodate, osmium tetroxide, oxygen-
Oshi 7 and its 74 compounds can be mentioned. A suitable diluent is any inert organic solvent.

Preferred diluents include ethyl acetate, ethanol, methanol, tetrahydrofuran, dichloromethane, dichloroethane, toluene and hishioxane, and mixtures thereof.

If appropriate, a reducing agent should be added during this reaction step before working up. Preferably, inorganic or organic (M
'i, yellow compounds can be used for this purpose. Particularly suitable are divalent organic sulfurs (17), such as valent dimethyl.

The reaction is generally carried out between -80°C and +50°C, but preferably between -80°C and 0°C.

According to the invention, in the conversion of compounds of formula (2) to compounds of formula (1), suitable reagents are any common oxidizing agents. Z that first induces dihydroxylation of the conjugated 21 bond
Preferably, the J reagent is used. This conversion can, if appropriate, be carried out analogously to known methods [E, G
,I) rain et al., ,J.C., ,S.

0°hern, comm, (1972) 229,
German national government “[Publication Specification No. 2.156.352
- No., A, Mu, /)oseet at,, Tet
rahedron 37, 2.321 (1981)
, J.S., Wells et al.
J, Δntibiot, 35189 (1982)).

Preferred oxidizing agents are potassium permanganate, sodium periodate, osmium tetroxide, and mixtures thereof.

Oxidizing agents such as lead tetraacetate, copper(II) acetate or N-halogenosuccinimide can also be used. Suitable solvents are any solvents which have a 11-degrading effect on the solvate and which primarily separates the oxidized butenoate group from the β-lactam in this manner. The following may be mentioned: water, methanol, ethanol, acetone, pyridine, triethylamine, dimethylformamide or mixtures thereof. If appropriate, basic or acidic auxiliaries can be used. These preferably include potassium carbonate, buffer solutions, organic amines such as triethylamine or pyridine, sulfuric acid, silicic acid or silica gel, or organic sulfonic acids. The reaction is preferably carried out between -40°C and +80°C. be exposed.

According to the invention, in the conversion of compounds of formula (3) to compounds of formula (1), suitable diluents are used for similar processes, such as for example European Patent No. 21.676 and German Pat.
Patent Application Publication Specification No. 4839.646 and R,/
ノ,G,Cooper et al,,ノ,,4m,C
hem.

Sac, 94, 1021 (1972°), any solvent suitable for producing solvate decomposition of the oxyamide structure having a solvate decomposition effect.

The solvents are preferably organic alcohols, primary amines and water, or mixtures of these with inert solvents, in particular methanol and other alcohols having 1 to 5 carbon atoms. If appropriate, you can list:
Basic or acidic adjuvants can be added to aid the reaction. The adjuvants preferably include alkali metal alcohols, alkali metal carbonates, buffer solutions, organic amines, carboxylic acids, sulfonic acids and inorganic protic acids. The following may be mentioned in particular: sodium methylate, potassium carbonate, weakly basic and weakly acidic buffer solutions, (ll!j acids, perchloric acid, phosphoric acid, silicic acid and silica gel. This reaction is preferably d-30℃ to +7
It is carried out between 0°C, but especially between 0°C and room temperature.

The following examples further illustrate and explain the invention.

Example 1 558 μl (4.0 mmol) of triethylamine were dissolved in diphenylmethyl 2-
((lI?, 5S)-3-phenyl-7-oxo-4-oxa-2,6-diazabicyclo(3,2,0)
hept-2-en-6-yl]-3-methylbut-3-
4.53.9 (10.0 mmol) of Enate was added to the solution and the mixture was stirred at room temperature for 6 hours. Ta. after that,
1300ml of ice-cold 1N11C mixture! and dichloromethane 50rn1. Extracted twice with It was dry. After evaporation of the solvent under vacuum and chromatography of the residue on 300 g of silica gel (
toluene:ethyl acetate 85:15), diphenylmethyl 2-[(l R,55) -3 as a colorless hard foam.
-Phenyl-7-oxo-4-oxa-2,6-diazabicyclo[3,2,0]]hept-2-en-6-yl]-3methylbut-2-eneate 3.81.9 (84
H) was obtained, Rfo, 54 (ether).

JR (KBr): 1783 (C=O, β-lactam)
, 1722 (C=O, ester), 1632cr
u-” (C=N).

'If-NAfR(2nOAfllz, Cr)C1
, ) : δ=1. ga (s, 311.C1l,
), 228 (8, 311, C1l, ), 5
．． 40 (s, J=411z, 177°11-5
), 6.08 (d, J=411z H17?
, 11-1), 6.95 (s, IN, C
00CIIPh2), 7. a-7,6 (71?,,
1311. C6rl, ), 7.95 (?l+
,,2H,o-phenyl-H).

Elemental analysis: CtsII, 4N, 04 (45'2-5
) Calculated value for: C74,32II 5.32
# 6.19 Actual value: C74, O 5.3 N6.
2 Example 2 Diphenylmethyl 2- in anhydrous dichloromethane 50me
[(IR,5s)-3-phenyl-7-oxo-4-oxa-2,6-diazabicyclo[320]hept-2-
En-6-yl]-3-methyl-2-eneate 1.5
01! An ozone-oxygen mixture was passed through a solution of (3.32 mmol) cooled to -70 DEG C. until it turned blue. This was followed by nitrogen bubbling for 10 minutes to remove excess ozone, followed by 1.95 mJ (26,5 mJ) of dimethyl sulfide.
2 mmol) was added at -70°C. Add this mixture to 10
Stirred for 30 minutes at °C and 1 hour at room temperature, then the solvent was evaporated under vacuum. Dichloromethane 7100 mJ
The solution was washed with saturated Na, 1CO3 solution and water and dried over MgSO4. The organic phase was evaporated under vacuum, the residue was taken up in chloroform, ether was added and the mixture was concentrated. Diphenylmethyl 2-[(17,5,5)-
3-phenyl-7-oxo-4-oxa-2,6-diazabicyclo[3,2,0]]hept-2-en-6-yl-2-nquinacetate 989 m9 (7 (1%)
was obtained, melting point IFt 2°C, RfO937 (ethyl acetate:hexanol:1) - [decomposes on contact with silica gel] - [α]20:I - 355° (i, o rl 6%, in chloroborum)
.

1R (KI'Jr)'', 1817 (C=O, β-lactam), 1754 (C-0, ester), 1712 (
C-0, amide, 1640 cm-1 (C-#).

'H-NMR (20 (JAflz, CI) CI,)
: δ=5.54'i (d, J=4.511z;
IH, H-5).

6.54 (d, J==4.5l7g, 1#, /7-1)
.

7.07 (g, 17/, C00CXPh2
), 7.2-7.6 (m, t13.11.C6H
), 7.9 (7?t, 27/, o-phenyl-77
).

+ M, S (70gυ):? 7+, /e=426(Af
) H total 19 value 426.4° Elemental analysis CvJI+8Ntos Calculated value for (426,4): (?70.42 B4.25 N6.5
7 Actual measurement candy: C70,4II 4.3 N 6.7
Example 3 h N)'O Co, C11) h.

3.35 me (24 mmol) of triethylamine was dissolved in 157! of anhydrous dichloromethane. diphenylmethyl 2-
((IR,55)-3-phenyl-7-oxo-4-oxa-2,6-diazabicyclo[320]hept-2-
En-6-yl]-3-methyl-3-eneate31.
68.9 (70 mmol) and the mixture was stirred at room temperature for 6 hours.

The mixture was then poured into cold lNlC, extracted in dichloromethane, the organic phase was washed with Nty, 11 CO, solution and dried over Mg, 50<''2. The drying agent was filtered off and the solution was evaporated under vacuum to approximately 11 g.

This mixture? Cool to -70°C under a cumulative atmosphere7, and ozone-oxygen until it turns blue. Tracing the Ih compound 1. Ta. Thereafter, excess ozone was removed by blowing with 9 elements for 10 minutes, and then 41 ml of dimethyl sulfide (5
59 mmol) was added. The mixture was stirred at -10° C. for 30 minutes and at room temperature for 1 hour, then the solvent was evaporated under vacuum.

The residue was dissolved in 600 ml of dichloromethane, the solution was washed with saturated Na1fCO, solution and AfQ
Dry over SO4. The organic phase was evaporated under vacuum, the residue was dissolved in a little chloroform, ether was added and the mixture was left to crystallize.

Diphenylmethyl 2- as colorless crystals with a melting point of 182°C.
((IR,5,5)-3-phenyl-7-oxo-4-
Oxa-2,6-diazabicyclo[3zO]hept-2
-en-6-yl]-2-oxoacetate 223Ii
(70.4chi) was obtained.

Example 4 36 m of a 0.002% solution of sodium methylate in methanol (! diphenylmethyl 2-((]R,5,5)-3-phenyl-7-oxo-4- in anhydrous methanol l OFt d Oxa-2,6-diazabicyclo[3,2,O)hept-2-en-6-yl]-2-
Oxoacetate 552 l19 (1,29 mmol)
and the mixture was pressed for 15 minutes at room temperature. Thereafter, 21 μe of glacial acetic acid was added and methanol was evaporated under vacuum. The residue was dissolved in dichloromethane 1 ml.
In the evening, pour this Sawa liquid into f1. -marked Na, lIC0° solution and washed with water and dried over M9SO4 t''11
It's 12. The solvent was evaporated under vacuum and the residue was
After chromatography on gel 20 g t:
ethyl acetate:hexane 6:4), as colorless crystals (I
R,5,5)-3-phenyl-7-oxo-4-oxa-2,6-diazabicyclo[3,2,0]]heptose 2
-ene 112m was obtained, melting point 159°C, Rfo, 2
3 (ether). [α]1,0=-1148° (0,
Section 836, in acetone).

JR (KBr): 1'712 (C=O, β-lacta 1 ), 1616m (C=O, C=N).

'II-NMR (200 Afll'z, DMSO):
δ=5.35 (dd, J=4Hz, J=4
Hz H1ff.

Jl-5), 6.11 (d, J=411z; lH
, H-1), 7.5-7.7 (tn,, 3H,
C0,111), 7.93(t++, 2//, o-
C? 6H5), 9.36 (d, J=411 Z; 1
// , Nll).

n1 calculated value for C, oII, N, O, 18Ft, 0
586S actual value 1880576 (mass spectrometry).

Example 5 Anhydrous methanol 750 r as described in Example 4
diphenylmethyl 2-[(IR,5S)
-3-phenyl-7-oxo-4-oxa-2,6-diazabicyclo[3,2,(1':lhept-2-en-6-yl]-2-oxoacedate 6.72.!9(1
After addition of 250 me and chamber 1 for 18 min, (I
B, 5.5)-phenyl-7-oxo-4-oxa-2,6-diazabicyclo[320]hept-2-
En got tl. 1 11 points 159-160°C0 Example 6 Methanol 60ml' and dichloromethane 407r11
diphenylmethyl 2-[(11?, 5S)
-3-phenyl-7-oxo-4-oxo-2,6-
diazabicyclo[3,2,0)hept-2-ene-〇-
A solution of 426 m9 (1 mmol) of Irk 2-oxoacetate (1 g of silica) in 50 ml of methanol
was added dropwise to the suspension, and the mixture was stirred at room temperature. At the end of the reaction (monitored by "m-layer chromatography"), the mixture was suction panned on a frit of diatomaceous earth;
Further processing was performed as described in Example 4. (11?, 5S)-phenyl-7-oxo-4- as colorless crystals
Oxa-2,6-diazabicyclo(3,2,0)hept-2-ene 71 was obtained. Melting point: 157°C.

Example 7 Water 7 me and water: yr5j/salt buffer (pH value?) 4
．． Potassium permanganate in 5 ml 297 my (1
A solution of diphenylmethyl 2-((1/<,5S)-3-phenyl-
7-oxo-4-oxa-2,6-diazabicyclo[3
20]hept-2-en-6-yl]-3-methy was added to a solution of 4) 452*+θ (t mmol) at 0'C over 30 minutes.

The mixture was stirred for a further 30 minutes at 0°C, then 100ml of ethyl acetate. was added, the acetone was evaporated using a Kojiku T, and the mixture was crushed under suction using a Kei-Uju. The organic phase was washed with saturated NaHCO, solution and water, and Mg
Dry over SO4. Purification was performed as described in Example 4. (1/?, 5S)-phenyl-7-oxo-4 as colorless crystals with melting point 158-159 °C]
-Oxa-2,6-diazabicyclo[320]hept-
2-ene 36rnQ (19%) was obtained.

Example 8 Diphenylmethyl 2- in dichloromethane 7 (1me)
((IR,5S)-3-7enyl-7-oxo-4-oxa-2,6-diazabicyclo(3,2,0)hept-
426 g of 2-en-6-yl]-2-oxoacetate
(lO mmol) was added to a suspension of 5 g of silica gel in 20 methanol and the mixture was stirred at room temperature for 8
Minute 1) Old stir. The mixture was then filtered under suction, the methanol was removed under vacuum and the residue was dissolved in dichloromethane. The solution was washed with saturated Na11CO3 solution and water and dried over MgSO4. Evaporate the solvent
After chromatography of the residue on silica gel 250I (hexane:ethyl acetate 2:3) as colorless crystals (1/?, 5S)-3-phenyl-7-oxo-4-oxa-2,6- diazabicyclo[3,2,
0]]Hepto2-en1.1? ,! i+62%) was obtained.

Example 9 (IS, 5/i Ri-3 in 75 mg of anhydrous dichloromethane)
-benzyl-6-(2-methylprop-1-enyl)-
4-Oxa-2,6-diazabicyclo(3,2,0)hept-2-ene-7-one [Stoudrey (1?, J
, 5toodley) et al., J.C.S., Per-
kinl 1974, 181) 2 56 l!
An ozone-oxygen mixture was passed through a solution of (lo mmol) cooled to -70°C until it turned blue. Thereafter, nitrogen was bubbled for 10 minutes, and then 5.9 rve (80 mmol) of dimethyl chloride was added at -70°C. The mixture was stirred at 0° C. for 1 hour and at room temperature for 1 hour,
It was then evaporated under vacuum. The residue was dissolved in dichloromethane, the solution was washed with saturated M ailc O3 solution and water, and dried over AfgSO4. The solvent was removed under vacuum and the residue was taken up with ether.

As colorless crystals with a melting point of 90-92°C (1,5,5R)
-3-be/zyl-6-formyl-4-oxa-2,6-
diazabicyclo(3,2,0)hept-2-ene-7-
1.2 g (52 g) of onion was obtained.

JR(Ki3r) 1821 (C=O, β-lactam).

1693 (C=O,N-Cll0), 1649cw-
'(C=N).

'H-NMR (200AfEz, CI)C
t, ) δ 3°75 (A, 1) system, J = 151
1z, 2H, CH,).

5.18 (d, J=4.5Hz, 111.H
-5), 6°15 (d, J=45H2, IH
, JT-1), 7.3 (7F+,, 5H, C61
1B), 8.74 (8, IH, CHO), fruit + HHIO 2 toodley (R, J, 5toodley), etc. J, C, S, Perkin, I (1979) 185
LO)-benidylamine (Δ
ld ~ rich) 3.7311 (25 mmol) was treated with oo .26.9 (38%) was obtained.

Dissolve the substance in 100 m of dry ff-tetrahydrofuran (with newly produced diphenyldiazomethane,
Continuously process until the color turns purple [7]. The solvent was evaporated and the residue was subjected to flash chroma 1-1 on 275 g of silica gel.
Separated by Claffy (toluene: ethyl acetate) 11
After sipping, diphenylmethyl-(2/?) is added as oil.
-3,3-dimethyltyrane-2-carboxylate 2
59 g (86 pieces) were obtained.

J R (NEET) 1730-174 (1 letter (C=O.

ester).

Turtle 7/-NkfR (200AfJ/z, CI)
C'l, ) δ : 1.68 (s, 311.
('H,), 1.71 (8,3//.

C11s), 3.35(s, IJI,
/7-2), 6.93(8,111,Co0C1
1ph2), 7.3-7.6 (m.

1nll, ph).

AfS (70eV): m, /e 315 (AI+)
; Total value: 315.4° Example 11 CO, C'll P /1. .

(l) in 5.5 me dry isadimethylformamide
I? .

5.5) -3-phenyl-7-oxo-4-oxa-2,6-diazabicyclo(3,2,0)hept-2-
(546 my (2,91) mol) and diphenylmethyl (2R)-3,3-dimethylthiane-2-carpoxyle)1. A stirred solution of nl[(3.2 mmol) KO dried at 1. Ip sium acetate (Aldric
h) 1.09 Fl was added. The water bath was removed and the mixture was stirred at room temperature for 11 hours. After this, mix the mixture with N
Poured into a mixture of n1fCO, solution and dichloromethane. The organic layer was separated, washed several times with water and dried over Argon4. The solvent was evaporated under J[Medium] and the residue was evaporated onto silica gel 67! After chromatography on l (toluene:ethyl acetate 3 nia) diphenylmethyl 2S-((IR,5S)-3-phenyl-7
-oxo-4-oxa-2,6-diazabicyclo[3,
2,0':lheptot-2-en-6-yl]-3-mercapto-3-methyl-butanoate 4701n9 (33
%)was gotten.

JR (K/lr) 1 7 7 6 (C=0
, β-lactam).

1727 (C-O, ester), 1629c++t
-1 (C=#).

'It-A'A(R(200A11lz)δ:1
．． 5,1.1(a, 3//each, CHa) + t't
(8+1tr+ClIC0OR), 5.47
(d, J=411z, tH.

11-5), 6.19 (d, J = 411
2, IH, H-1), 6.93 (s, x
ll, cilph, ), 7.3-7.6 (m,
1311. J) h, ) , 7.9 (m, 2
II.

C'O, C"horn ph! Diphenylmethyl 2 in dry dichloromethane 50ml!
5-[(1/?, 5S)-3-phenyl-7-oxo-4-oxa-2,6-diazabicyclo(:3.2.0
) hept-2-en-6-yl]-3-mercapto-3
-Methyl-butanoate 4.87 g (10 mmol)
To the stirred solution of was added at room temperature 86 μg (0.7 mmol) of boron trifluoride etherate. The clear solution was stirred at room temperature for 4.5 hours (monitored by thin layer chromatography) and then 98 μe (0.7 mmol) of triethylamine was added to neutralize the Lewis acid catalyst. The reaction mixture was cooled to approximately +5 °C in a water bath and heated to 8
2% fu+t-chloroperbenzoic acid 4.1! (20 mmol) was added in one portion. Add this mixture to +5 to +10'C.
It was stirred for 25 h at 200 ml and then poured into a mixture of 300 ml of saturated Na,//CO3 solution and 30 me of 20% Na, SO3 solution. Separate the organic layer for 1'Jlc 1. ,, washed with water, and -CAf q S 0. It was dried at 1-. After evaporation of the solvent under vacuum and chromatography on silica gel 400y (toluene:ethyl acetate)
:l), colorless crystals with FA'j point of 157-158℃ and 1
．． 4.12 g (82%) of diphenylmethyl (5R,6S)-6-penzoylamino-1-oxo-penicillane-3-carboxylate were obtained.

JR (CHCI,) 1795 (c=0.β-lactam)
, 1748 (C-0, ester), 1672 cm-'
(C=O, amide).

'//-N MR(200 MII z,
CI) Cl, ) δ : 0.92 (a, 3
1f, C1l, ), 1.64 (s, 3H
.

C1l, ), 4.61 (8, IN, CD-Co, R)
.

5.14 (d, , 1 = 211z, 1/I,
5-If), 5.40(dd, J=211z
, J=IHz, III, 6-. 11).

6.91 (S', 111.CllPh, ),
7.3-7.5 (m.

13H, II aromatic), 7.64 (d, J
=711Z.

NIP), 7.8 (m, 211, orthobenzoyl-H).

Elemental analysis: C'2. H,, N2n, S (502,6
): Hln value for C66,9II Fi2A'
5.6 S6.4 Actual D River I Nao: C66,611
5,1# 5. 6 S6. 4-1 Compound '1 Of course (6R, 7R) -7-(2-carboxy-2-(4-hydroxyphenyl)acetamide]-7
-Medoxy 3-(l-methyl-5-tetrazolylthiomethyl)-8-okino-5-oxa-1-azabinclo(4,2,0) converted to oct-2-ene-2-carboxylic acid. [M, Narisada, etc.,
J. Antibiot, 35463 (1982)
and references cited herein].

Does this specification and examples fit? This is provided for clarity only and is not intended to limit the invention, and is subject to various modifications and changes.
, it will be appreciated that this can be done without departing from l/It.

Claims (1)

[Claims] 1. General formula (1) In the formula, R is hydrogen or optionally substituted alkyl, alkenyl, alkynyl, aralkyl, aryl,
Representing heteroaryl, heteroaralkyl, aryloxyalkyl, heteroaryloxyalkyl, alkoxyalkyl, arylthioalkyl, heteroarylthioalkyl, alkylthioalkyl, alkoxy, aryloxy, alkylthio or arylthio. 2 R is an optionally substituted C3-C,-alkyl group, an optionally substituted phenyl group, an optionally substituted benzyl group, an optionally substituted phenoxymethyl group, Represents a furyl, chenyl, thiazolyl, isoxazolyl, pyridyl, pyrimidyl, pyrazolyl, uracil, thiadiazolyl, tetrazolyl or 1-pyranyl group which may be optionally substituted! t
9. The compound according to item 1. 3(a) General formula (2) In the formula, R hydrogen or optionally substituted alkyl, alkenyl, alkynyl, aralkyl, aryl,
heteroaryl, heteroaralkyl, aryloxyalkyl, heteroaryloxyalkyl, alkoxyalkyl, arylthioalkyl, heteroarylthioalkyl, alkylthioalkyl, alkoxy, aryloxy, alkylthio or arylthio, and Co and E are acid functional groups. The N-substituted oxazolinoazetidinone of Co, II, representing the desired ester functionality, is solvated in a suitable solvent, if appropriate in the presence of an acid binder. (b) an oxyamide of the general formula (3) in which R and Co and E have the meanings given in 112. Compounds of the general formula (1), characterized in that they are converted under solvolysis conditions in a suitable solvent, if appropriate in the presence of an acid or a base, in which R has the meaning given above. manufacturing method. 4. The method according to claim 3, wherein the oxidizing agent in method (a) is potassium permanganate, sodium periodate or osmium tetroxide. 5. The method according to claim 3, wherein water, a primary amine or an alcohol is used as the solvent in method (b). 6. The method according to claim 3 or 4, wherein the reaction (a) is carried out at -40°C to +80°C. 7. The method according to claim 3 or 5, wherein the reaction (b) is carried out at 0°C to room temperature. 8. Use of a compound according to claim 1 in the manufacture of β-lactam antibiotics.